Propofol (2,6-diisopropyl phenol, C12H18O) is a widely used drug for both intravenous anesthesia induction, as well as an agent for anesthesia maintenance by infusion administration. Propofol popularity has been gained due to its various advantages. Among the positive properties it offers is its rapid onset and short duration of action due to its low tendency to accumulate in the body (high clearance rate and relatively fast elimination due to its short half-life), combined with smooth and excellent emergence from anesthesia, with low incidence of postoperative nausea and vomiting. The fact that recovering from propofol anesthesia has minimal side effects had expanded its use from solely an anesthetic drug to a sedative-hypnotic agent used in the intensive care units, in outpatient procedures, and in adults on life-support systems.
Propofol is a lipophilic oil with virtually zero water solubility (150 μg/liter) and is therefore administered intravenously (IV) in an emulsion formulation. Development of propofol injected formulation has been a great challenge. The first clinical trials were conducted in Europe in 1977, using 1 and 2 wt % propofol preparations formulated with Cremophor EL and ethanol. This formulation had shown high anaphylaxis incidences causing the withdrawal of propofol from further development. Thereafter, many attempts to develop a formulation with minimal side effects and appropriate anesthetic profile, while maintaining the formulation's physical and chemical stability, were conducted. Finally, an oil-in-water (lipid-based) propofol emulsion was developed and evaluated for human use in clinical trials in Europe in 1983 and in the United States in 1984. This formulation was launched in the United Kingdom and New Zealand in 1986 and in the U.S. in 1989. In 1999 a generic lipid-based emulsion was also introduced to the U.S. market. In spite of FDA and European approvals of those emulsions, several major drawbacks were reported: physical emulsion instability, pain upon injection, hyperlipidemia (due to the relatively high lipid content) and increase possibility of microorganism contamination leading to blood sepsis complications and even death. In addition, propofol's sensitivity to oxidation and the emulsion's composition which is a substrate for proliferation of bacteria often dictates complicated production procedures and impose limitations on storage conditions and restrictions of usage after opening the emulsion vial. Further, the instability of the emulsion might cause, within time, to the formation of large droplets (over 500 nm) putting patients at risk, since the fused drops are too large to pass through the blood capillaries without causing emboli; the large fat globules formation is also extremely dangerous as it may remain relatively longer in the patient's organs, such as the lungs, spleen and liver, causing organ toxicity.
Contrary to most compounds administered intravenously, which are typically electrically charged molecules, propofol is not charged and therefore cannot be administered as an aqueous salt. Propofol's high lipophilicity and limited miscibility (150 μg/liter) has forced its formulation to be a lipid-based emulsion, containing soybean oil, egg yolk lecithin and glycerol. Although solving propofol's solubility problems, a substantial number of undesirable properties had been attributed to this large droplets emulsion system. The formulation had presented severe allergic reactions, physical instability and substantial pain during IV injection. In intensive care units, where propofol is used for long-term administration, the potential to develop hyperlipidemia is significant. This complication has been named “propofol infusion syndrome” and can often lead to lethal metabolic disorders. Moreover, the lipid formulation had shown a high risk of bacteremia due to its association with microbiology contamination during manufacture or throughout its preparation prior to its use. The failure to overcome the possibility of microbial growth, has led to the risk of patients developing high fever, infections, sepsis and even death. The high cost in propofol emulsion manufacturing, compared with alternative induction anesthesia agents, as well as the requirements to use propofol within 6 hours from opening had caused many propofol formulation manufacturers to seize production.
Because of its properties, propofol formulation presents a significant challenge to physical and colloid chemistry scientists. Some of the undesirable features of propofol are formulation-dependent. Consequently, there is a significant interest in the development of new formulations that will have minimal side effects and undesirable properties, however, will retain propofol's beneficial kinetic profile and its desirable anesthetic effect.
Microemulsions (MEs) can be considered as vehicles for drug delivery due to their spontaneous formation, high solubilization capacity and physical stability [1]. Attempts to formulate propofol in classical oil-in-water microemulsions have yet to be accepted by the pharmaceuticals industry or the FDA. To date, no acceptable formulations of fully dilutable propofol microemulsions that exhibit all the prerequisites for IV propofol preparations, e.g. dilutable by an aqueous phase, proper osmolarity, droplet size distribution, stability, microbiology clearance, pain-less, etc. were developed, which are essential for proper dispersion in blood without causing side effects or decomposing physically or chemically.
Nano-sized self-assembled liquids (NSSLs) are an advanced category of delivery vehicles. The NSSLs are self-assembled microemulsions systems of nanodroplets, comprising surfactants and oil. Such systems may comprise, at times, additional components such as co-surfactants, solvents, co-solvents and other additives. These self-assembled microemulsions may be in the form of concentrates that can be fully and progressively diluted with aqueous phase to form microemulsions. Upon formation, these systems self-assemble into reverse micelles; upon dilution with water or aqueous solutions, water-swollen micelles or water-in-oil nanodroplets are formed, being able to invert into bicontinuous mesophases in the presence of an aqueous phase, e.g. water. Upon further dilution, they undergo inversion (umbrella type inversion) into oil-in-water droplets. Such systems have been previously studied and their ability to solubilize non-soluble drugs and nutraceuticals has been demonstrated [2-7]. However, propofol's has unique chemical structure, being very lipophilic, and thus weakly interacts with the surfactant's head-groups and requires use of additional hydrophilic compounds to dehydrate the head-groups of the surfactants for obtaining elasticity, curvature and zero interfacial tension of the system. As a consequence to its unique properties, not every dilutable system provides for a stable propofol microemulsion that is suitable for parenteral administration.
In the present invention, nanometric structures, i.e. the improved self-assembled systems, are specially designed to load propofol in an oil concentrate, which can then be easily diluted “on demand” and as per application with any type of aqueous solution (buffer, water for injection, saline, isotonic mixtures and others). Unique tailoring of suitable self-assembled formulations for propofol according to the invention enable the drug-loaded concentrated formulation to be further diluted with fluid, such as the bloodstream, thereby forming clear (transparent), stable mixtures without phase separation and/or drug precipitation. These systems are isotropic, thermodynamically stable, presenting high solubilization capacity, and have an increased ability to improve the bioavailability of propofol. Other advantages of this unique formulation will become apparent from the disclosure below.